Food Anticipatory Activity on Circadian Time Scales Is Not Dependent on Central Serotonin: Evidence From Tryptophan Hydroxylase-2 and Serotonin Transporter Knockout Mice

Creators: Gallardo, Christian M.; Martin, Camille S.; Steele, Andrew D.

Abstract

A number of studies implicate biogenic amines in regulating circadian rhythms. In particular, dopamine and serotonin influence the entrainment of circadian rhythms to daily food availability. To study circadian entrainment to feeding, food availability is typically restricted to a short period within the light cycle daily. This results in a notable increase in pre-meal activity, termed "food anticipatory activity" (FAA), which typically develops within about 1 week of scheduled feeding. Several studies have implicated serotonin as a negative regulator of FAA: (1) aged rats treated with serotonin 5-HT2 and 3 receptor antagonists showed enhanced FAA, (2) mice lacking for the 2C serotonin receptor demonstrate enhanced FAA, and (3) pharmacologically increased serotonin levels suppressed FAA while decreased serotonin levels enhanced FAA in mice. We sought to confirm and extend these findings using genetic models with impairments in central serotonin production or re-uptake, but were surprised to find that both serotonin transporter (Slc6a4) and tryptophan hydroxylase-2 knockout mice demonstrated a normal behavioral response to timed, calorie restricted feeding. Our data suggest that FAA is largely independent of central serotonin and/or serotonin reuptake and that serotonin may not be a robust negative regulator of FAA.

Additional Information

© 2020 Gallardo, Martin and Steele. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Received: 11 February 2020; Accepted: 13 August 2020; Published: 11 September 2020. We are grateful to Michael Clarke (University of Washington, Seattle) for providing the Tph2 knockout mice, Raymond Johnson of the Vanderbilt Neurochemistry Core Lab for HPLC measurements of serotonin from tissue punches, and to the peer reviewers and editor for many helpful suggestions for improving the manuscript. Data Availability Statement: The datasets generated for this study are available on request to the corresponding author. Ethics Statement: The animal study was reviewed and approved by the California Institute of Technology Institutional Animal Care and Use Committee. Author Contributions: AS and CG designed the experiments. AS, CG, and CM performed the experiments. AS and CM analyzed the data. AS wrote the manuscript. All authors approved the final version. This research was supported by the New Investigator Award from the Ellison Medical Foundation to AS, the Caltech Broad Fellows in Brain Circuitry Program, and by the National Institute of General Medical Sciences of the National Institutes of General Medical Sciences of the National Institutes of Health under Award Number SC3GM125570. The content was solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Neurochemistry Core is supported by the Vanderbilt Brain Institute and the Vanderbilt Kennedy Center. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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